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2.4 Conclusions, Hypotheses, and Controversies
We have described three extracellular nucleotide-initiated signaling pathways, lead-
ing to activation of FAK, AMPK and eNOS. Moreover, we showed that purine
nucleotides and adenosine increase levels of ATPi in EC. Therefore we hypothe-
size that extracellular nucleotides may regulate various EC functions, including cell
migration, proliferation and apoptosis (Fig. 2.4).
Fig. 2.4 A scheme of the extracellular nucleotide/adenosine-induced signaling pathways leading
to activation of AMPK and eNOS, and an increase in the intracellular ATP (ATPi) concentration,
which may regulate EC proliferation and apoptosis
These three signaling pathways are linked by their dependence on [Ca 2+ ] i .
Indeed, chelation of intracellular Ca 2+ inhibits nucleotide-induced activation of
FAK, AMPK, and eNOS. However, these signaling pathways diverge downstream,
possibly due to compartmentalization of purinergic signaling. Otherwise, AMPK,
which has been shown by other studies to be an upstream kinase that activates eNOS,
would also phosphorylate eNOS on Ser-1177 in our experimental system.
Our results obtained with pharmacological ligands and antagonists indicate that
P2Y1 and P2Y2 receptors are the main functional P2 receptors in HUVECs,
however, these data need to be validated by additional experiments with genetic
effectors, i.e. , specific siRNA to suppress expression of individual P2 receptor
subtypes. Our studies have been restricted to HUVECs and HCAECs, however, as
suggested by other reports, ECs originating from other vascular beds may express
different repertoires of P2 receptor subtypes and thus respond to extracellular
nucleotides differently. This intriguing aspect of purinergic signaling awaits further
investigations as well.
Currently available data on the signaling effects of extracellular nucleotides
were obtained from studies of ECs from different species, such as human, bovine,
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